Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

Abstract

BackgroundMyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients.MethodsScreening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.Results16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].ConclusionsMutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

“…31 This intronic variant was originally reported as VUS; but on subsequent predictive testing, it was found to be present in the affected mother and also the two affected siblings and was subsequently upgraded to a pathogenic variant. Proband PI1, with severe HCM, had two reported variants on genetic testing, i.e., Glu123Gln in TNNI3 and c.*89G>A in MYL3, which were classified as a pathogenic mutation and a VUS, respectively, at diagnosis.…”

Next-generation Sequencing in the Clinical Decision Making in Hypertrophic Cardiomyopathy

“…Taken together, the mutation forming allele will provide a much shorter protein with Cterminal fragment lost. A mutation in similar location has already been published (K600fs); with this mutation, atrial fibrillation was diagnosed at young age but no any other specific sign or clinical symptoms including sudden cardiac death was observed [14].…”

Analysis of variants in the HCN4 gene and in three single nucleotide polymorphisms of the CYP3A4 gene for association with ivabradine reduction in heart rate: A preliminary report

“…HT -hypertension; LVEF -left ventricular ejection fraction; M -male; MI -myocardial infarction; NYHA -New York Heart Association; SBP -systolic blood pressure www.cardiologyjournal.org BACC3 (GE Healthcare), as previously described [18,19]. The variant analysis was carried out by a polymerase chain reaction (PCR) followed by direct sequencing [18,19].…”

“…The variant analysis was carried out by a polymerase chain reaction (PCR) followed by direct sequencing [18,19]. The primers were designed using Primer3 software (http://bioinfo.ut.ee/ /primer3-0.4.0/) ( Table 2).…”